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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene.

ABSTRACT: Peroxisome proliferator-activated receptor (PPAR)-? is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-? agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-? in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-? gene (ePPAR?(-/-) mice) were generated using loxP/Cre technology. ePPAR?(-/-) mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPAR?(-/-) mice (P < 0.05). In ePPAR?(-/-) mouse aortas, phosphorylation of endothelial NO synthase at Ser(1177) was significantly decreased (P < 0.05). However, basal levels of cGMP were unexpectedly increased (P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPAR?(-/-) mice (P < 0.05). Most notably, endothelium-specific deletion of the PPAR-? gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta (P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPAR?(-/-) mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-?-deficient arteries to oxidative stress and vascular dysfunction.

SUBMITTER: d'Uscio LV

PROVIDER: S-EPMC3962632 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene.

d'Uscio Livius V LV He Tongrong T Santhanam Anantha Vijay R AV Tai Li-Jung LJ Evans Ronald M RM Katusic Zvonimir S ZS

American journal of physiology. Heart and circulatory physiology 20140131 7

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ(-/-) mice) were generated using loxP/Cre technology. ePPARδ(-/-) mice were no ...[more]

PMID: 24486511

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Project description:ObjectiveAngiotensin II (AngII) has been shown to regulate angiogenesis and at high pathophysiological doses to cause vasoconstriction through the AngII receptor type 1. Angiotensin 1 to 7 (Ang-(1-7)) acting through the Mas1 receptor can act antagonistically to high pathophysiological levels of AngII by inducing vasodilation, whereas the effects of Ang-(1-7) signaling on angiogenesis are less defined. To complicate the matter, there is growing evidence that a subpressor dose of AngII produces phenotypes similar to Ang-(1-7).Approach and resultsThis study shows that low-dose Ang-(1-7), acting through the Mas1 receptor, promotes angiogenesis and vasodilation similar to a low, subpressor dose of AngII acting through AngII receptor type 1. In addition, we show through in vitro tube formation that Ang-(1-7) augments the angiogenic response in rat microvascular endothelial cells. Using proteomic and genomic analyses, downstream components of Mas1 receptor signaling were identified, including Rho family of GTPases, phosphatidylinositol 3-kinase, protein kinase D1, mitogen-activated protein kinase, and extracellular signal-related kinase signaling. Further experimental antagonism of extracellular signal-related kinases 1/2 and p38 mitogen-activated protein kinase signaling inhibited endothelial tube formation and vasodilation when stimulated with equimolar, low doses of either AngII or Ang-(1-7).ConclusionsThese results significantly expand the known Ang-(1-7)/Mas1 receptor signaling pathway and demonstrate an important distinction between the pathological effects of elevated and suppressed AngII compared with the beneficial effects of AngII normalization and Ang-(1-7) administration. The observed convergence of Ang-(1-7)/Mas1 and AngII/AngII receptor type 1 signaling at low ligand concentrations suggests a nuanced regulation in vasculature. These data also reinforce the importance of mitogen-activated protein kinase/extracellular signal-related kinase signaling in maintaining vascular function.

Dataset Information

Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-? gene.

Publications

Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene.

Similar Datasets

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